Retinoic acid and its natural and synthetic analogs exert a wide array of biological effects. They have been shown to affect cellular growth and differentiation and are promising drugs for the treatment of several cancers.
U.S. Pat. No. 5,618,839 and EP 661,259 A1 published Jul. 5, 1995 disclose a series of substituted (5,6)-dihydronapthalenyl compounds of the formula ##STR1##
or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof, in which
X is --O--CO--, --NH--CO--, --CS--NH--, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --C.ident.--C--, --CH.sub.2 --NH--, --COCH.sub.2 --, --NHCS--, --CH.sub.2 S--, --CH.sub.2 O--, --OCH.sub.2 --, --NHCH.sub.2 -- or --CR.sup.5.dbd.CR.sup.6 --; PA1 R.sup.m and R.sup.k are independently hydrogen, halogen, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 -alkyloxy or nitro; PA1 n is zero or one; PA1 R.sup.4 is --(CH.sub.2).sub.t --Y, C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl; PA1 R.sup.1 is --CO.sub.2 Z, C.sub.1-6 alkyl, CH.sub.2 OH, --CONHR.sup.y, or CHO; PA1 R.sup.2 and R.sup.3 are independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.a and R.sup.b are independently hydrogen or C.sub.1-6 alkyl; but when n is one, R.sup.a and R.sup.b together can form a radical of the formula ##STR2## PA1 Y is naphthyl or phenyl, both radicals can be optionally substituted with one to three same or different C.sub.1-6 alkyl or halogen; PA1 Z is hydrogen or C.sub.1-6 alkyl; PA1 R.sup.5, R.sup.6 and R.sup.y are independently hydrogen or C.sub.1-6 alkyl; and PA1 t is zero to six. PA1 X is --O--CO--, --NH--CO--, --CS--NH, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --C.ident.C, --CH.sub.2 --NH--, --COCH.sub.2 --, --NHCS--, --CH.sub.2 S--, --CH.sub.2 O--, --OCH.sub.2 --, --NHCH.sub.2 -- or --CR.sup.5.dbd.CR.sup.6 --; PA1 R.sup.m and R.sup.k are independently hydrogen, halogen, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkyloxy or nitro; PA1 n is zero or one; PA1 R.sup.4 is --(CH.sub.2).sub.t --Y; PA1 R.sup.1 is --CO.sub.2 Z, --C.sub.1-6 alkyl, CH.sub.2 OH, --CONHR.sup.y or CHO; PA1 R.sup.2 and R.sup.3 are independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.a and R.sup.b are independently hydrogen or C.sub.1-6 alkyl; but when n is one, R.sup.a and R.sup.b together can form a radical of the formula ##STR4## PA1 Y is phenyl or naphthyl and both radicals can be optionally substituted with one to three same or different C.sub.1-6 alkyl or halogen groups; PA1 Z is hydrogen or C.sub.1-6 alkyl; PA1 R.sup.5, R.sup.6 and R.sup.y are independently hydrogen or C.sub.1-6 alkyl; and PA1 t is zero to six. PA1 R.sub.2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF.sub.3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; PA1 R.sub.3 is hydrogen, lower alkyl of 1 to 6 carbons or F; PA1 m is 0, 1, 2 or 3; PA1 o is 0, 1, 2 or 3; PA1 Z is --C.ident.C--, PA1 Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R.sub.2 groups, or PA1 when Z is --(CR.sub.1.dbd.CR.sub.1).sub.n' and n' is 3, 4 or 5, then Y represents a direct valence bond between said (CR.sub.1.dbd.CR.sub.1).sub.n' group and B; PA1 A is (CH.sub.2).sub.q where q is 0 or an integer of 1-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, or alkynyl having 2-6 carbons and 1 or 2 triple bonds; PA1 B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, CONR.sub.9 R.sub.10, --CH.sub.2 OH, --CH.sub.2 OR.sub.11, CH.sub.2 OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CHOR.sub.13 O, --COR.sub.7, CR.sub.7 (OR.sub.12).sub.2, CR.sub.7 OR.sub.13 O, or tri-lower alkylsilyl, where R.sub.7 is an alkyl, cycloalkyl or alkenyl group having 1-5 carbons, R.sub.8 is an alkyl group of 1 to 10 carbons, or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R.sub.11, is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13 is a divalent alkyl radical of 2-5 carbons; and PA1 R.sub.14 is (R.sub.15).sub.r -phenyl, (R.sub.15).sub.r -naphthyl or (R.sub.15).sub.r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is 0 or an integer of 1-5; and R.sub.15 is independently H, F, Cl, Br, I, NO.sub.2, N(R.sub.8).sub.2, N(R.sub.8)COR.sub.8, NR.sub.8 (CON(R.sub.8).sub.2, OH, OCOR.sub.8, OR.sub.8, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 2 to 10 carbons and 1 to 3 double bonds, alkynyl group having 2-10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons. PA1 X is [C(R.sub.1).sub.2 ].sub.n, where R.sup.1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2; PA1 R.sub.2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF.sub.3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; PA1 R.sub.3 is hydrogen, lower alkyl of 1 to 6 carbons or F; PA1 m is an integer having the value of 0-3; PA1 o is an integer having the value of 0-3; PA1 Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R.sub.2 groups; PA1 A is (CH.sub.2).sub.q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; PA1 B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, CONR.sub.9 R.sub.10, --CH.sub.2 OH, CH.sub.2 OR.sub.11, CH.sub.2 OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CHOR.sub.13 O, --COR.sub.7, CR.sub.7 (OR.sub.12).sub.2, CR.sub.7 OR.sub.13 O, or tri-lower alkylsilyl, where R.sub.7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R.sub.8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R.sub.11 is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13 is divalent alkyl radical of 2-5 carbons, and PA1 R.sub.14 is (R.sub.15).sub.r -phenyl, (R.sub.15).sub.r -naphthyl, or (R.sub.15).sub.r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and PA1 R.sub.15 is independently H, F, Cl, Br, I, NO.sub.2, N(R.sub.8).sub.2, N(R.sub.8)COR.sub.8, NR.sub.8 CON(R.sub.8).sub.2, OH, OCOR.sub.8, OR.sub.8, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons; PA1 R.sub.16 is H, lower alkyl of 1 to 6 carbons; PA1 R.sub.17 is H, lower alkyl of 1 to 6 carbons, OH or OCOR.sub.11 and PA1 p is zero or 1, with the proviso that when p is 1 then there is no R.sub.17 substituent group, and m is an integer between 0 and 2. PA1 X is --O--CO--, --NH--CO--, --CS--NH, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --C.ident.C--, --CH.sub.2 --NH--, --COCH.sub.2 --, --NHCS--, --CH.sub.2 S--, --CH.sub.2 O--, --OCH.sub.2 --, --NHCH.sub.2 -- or --CR.sup.5.dbd.CR.sup.6 --; PA1 R.sup.m and R.sup.k are independently hydrogen, halogen, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkyloxy or nitro; PA1 n is zero or one; PA1 A is --NH(CH.sub.2).sub.m --, --S--, --SO--, --SO.sub.2 --, --O--, --C.ident.C--, --CR.sup.8 R.sup.9, --CR.sup.8.dbd.CR.sup.9 --, phenyl, phenyl substituted by a C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, CO.sub.2 R.sup.8, --(CH.sub.2).sub.m OR.sup.8, --(CH.sub.2).sub.m NR.sup.9 R.sup.8, or --COR.sup.10 group, naphthyl, naphthyl substituted by a C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, CO.sub.2 R.sup.8, --(CH.sub.2).sub.m OR.sup.8, --(CH.sub.2).sub.m NR.sup.8 R.sup.9 or --COR.sup.10, or heteroaryl; PA1 Q is phenyl, naphthyl or heteroaryl, said phenyl, naphthyl or heteroaryl group being optionally substituted by one to three same or different C.sub.1-6 alkyl, C.sub.1-6 fluoroalkyl, C.sub.1-6 alkoxy, halogen, CO.sub.2 R.sup.11, --(CH.sub.2).sub.q OR.sup.11, --(CH.sub.2).sub.q NR.sup.11 R.sup.12, --NHCOR.sup.13 or --COR.sup.13 with the proviso that when A is --S--, --SO--, --SO.sub.2 -- or --O--, then Q is a phenyl, naphthyl or heteroaryl group substituted by one to three halogen, C.sub.1-6 fluoroalkyl, CO.sub.2 R.sup.11, --(CH.sub.2).sub.q OR.sup.11, --(CH.sub.2).sub.q NR.sup.11 R.sub.12, --NHCOR.sup.13 or --COR.sup.13 ; PA1 R.sup.5 and R.sup.6 are each independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.8 and R.sup.9 are each independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.10 and R.sup.13 are each independently hydrogen, C.sub.1-6 alkyl or C.sub.1-6 fluoroalkyl; PA1 R.sup.11 and R.sup.12 are each independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.a and R.sup.b are independently hydrogen or C.sub.1-6 alkyl; but when n is one, PA1 R.sup.a and R.sup.b together can form a radical of the formula ##STR8## PA1 Z is hydrogen, C.sub.1-6 alkyl, benzyl, p-methoxybenzyl, allyl or trimethylsilylethyl; PA1 m and q are independently 0 to 2; PA1 p is 0 or 1 with the proviso that when p is 0 then Q is phenyl, naphthyl or heteroaryl substituted by one to three --(CH.sub.2).sub.q OR.sup.11, --(CH.sub.2).sub.q NR.sup.11 R.sup.12, or --COR.sup.13 PA1 R.sup.2 and R.sup.3 are each independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.1 is --CO.sub.2 Z, C.sub.1-6 alkyl, --CH.sub.2 OH, --CONHR.sup.7 or CHO; PA1 R.sup.7 is hydrogen or C1-6 alkyl; PA1 R.sub.1 is hydrogen or alkyl of 1 to 10 carbons; PA1 R.sub.2 and R.sub.3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; PA1 m is an integer having the value of 0-3; PA1 o is an integer having the value 0-3; PA1 Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R.sub.2 groups; PA1 A is (CH.sub.2).sub.n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; PA1 B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, CONR.sub.9 R.sub.10, --CH.sub.2 OH, --CH.sub.2 OR.sub.11, --CH.sub.2 OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CHOR.sub.13 O, --COR.sub.7, CR.sub.7 (OR.sub.12).sub.2, CR.sub.7 OR.sub.13 O, or tri-lower alkylsilyl, where PA1 R.sub.7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R.sub.8 is an alkyl group of 1 to 10 carbons, or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R.sub.11 is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sup.13 is divalent alkyl radical of 2-5 carbons and PA1 R.sub.22 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C.sub.1 -C.sub.10 -alkylphenyl, naphthyl, C.sub.1 -C.sub.10 -alkylnaphthyl, phenyl, C.sub.1 -C.sub.10 alkyl, naphthyl-C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 -alkenylphenyl having 1 to 3 double bonds, C.sub.1 -C.sub.10 -alkenylphenyl having 1 to 3 triple bonds, phenyl-C.sub.1 -C.sub.10 alkenyl having 1 to 3 double bonds, phenyl-C.sub.1 -C.sub.10 alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds, where the acyl group is represented by COR.sub.14, CN, CON(R.sub.1).sub.2, (CH.sub.2).sub.p CO.sub.2 R.sub.8 where p is an integer between 0 to 10, or R.sub.22 is aminoalkyl or thioalkyl of 1 to 10 carbons, or a 5 or 6 membered heteroaryl group optionally substituted with a C.sub.1 to C.sub.10 alkyl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, or R.sub.22 is represented by (CH.sub.2).sub.p XR.sub.1 or by (CH.sub.2).sub.p NR.sub.1 R.sub.2 ; where X is O or S, the R.sub.14 group is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C.sub.1 -C.sub.10 -alkylphenyl, naphthyl, C.sub.1 -C.sub.10 -alkylnaphthyl, phenyl-C.sub.1 -C.sub.10 alkyl, or naphthyl-C.sub.1 -C.sub.10 alkyl PA1 Z is --N.dbd.N--, PA1 R.sub.2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF.sub.3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; PA1 R.sub.3 is hydrogen, lower alkyl of 1 to 6 carbons or F; PA1 m is an integer having the value of 0-3; PA1 o is an integer having the value of 0-3; PA1 Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R.sub.2 groups, or PA1 when Z is --(CR.sub.1.dbd.CR.sub.1).sub.n' -- and n' is 3, 4 or 5 then Y represents a direct valence bond between said (CR.sub.2.dbd.CR.sub.2).sub.n' group and B; PA1 A is (CH.sub.2).sub.q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; PA1 B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, CONR.sub.9 R.sub.10, --CH.sub.2 OH, --CH.sub.2 OR.sub.11, --CH.sub.2 OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CHOR.sub.13 O, --COR.sub.7, CR.sub.7 (OR.sub.12).sub.2, CR.sub.7 OR.sub.13 O, or Si(C.sub.1-6 alkyl).sub.3, where R.sub.7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R.sub.8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R.sup.11 is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13 is divalent alkyl radical of 2-5 carbons; PA1 X.sub.2 is O, S, SO or SO.sub.2, and PA1 R.sub.20 is Si(C.sub.1-6 alkyl).sub.3, R.sub.14, COR.sub.14, SO.sub.2 R.sub.21, where R.sub.14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C.sub.1 -C.sub.10 -alkylphenyl, naphthyl, C.sub.1 -C.sub.10 -alkylnaphthyl, phenyl-C.sub.1 -C.sub.10 -alkyl, naphthyl-C.sub.1 -C.sub.10 -alkyl, or R.sub.20 is hydroxyalkyl, aminoalkyl or thioalkyl having 1 to 10 carbons, and R.sub.21 is alkyl of 1 to 10 carbons, fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, C.sub.1 -C.sub.10 -alkylphenyl and phenyl-C.sub.1 -C.sub.10 -alkyl, and retinoids of the formula ##STR11## PA1 Z is --N.dbd.N--, PA1 R.sub.2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF.sub.3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; PA1 R.sub.3 is hydrogen, lower alkyl of 1 to 6 carbons or F; PA1 m is an integer having the value of 0-3; PA1 o is an integer having the value of 0-3; PA1 Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R.sub.2 groups, or PA1 when Z is --(CR.sub.1.dbd.CR.sub.1).sub.n' -- and n' is 3, 4 or 5 then Y represents a direct valence bond between said (CR.sub.2.dbd.CR.sub.2).sub.n' group and B; PA1 A is (CH.sub.2).sub.q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; PA1 B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8, CONR.sub.9 R.sub.10, --CH.sub.2 OH, --CH.sub.2 OR.sub.11, --CH.sub.2 OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CHOR.sub.13 O, --COR.sub.7, CR.sub.7 (OR.sub.12).sub.2, CR.sub.7 OR.sub.13 O, or Si(C.sub.1-6 alkyl).sub.3, where R.sub.7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R.sub.8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R.sub.11 is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13 is divalent alkyl radical of 2-5 carbons; and PA1 R.sub.14 is (R.sub.15).sub.r -substituted alkyl of 1-6 carbons, (R.sub.15).sub.r -substituted alkenyl of 1-6 carbons and 1 or 2 double bonds, (R.sub.15).sub.r -substituted alkynyl of 1-6 carbons and 1 or 2 triple bonds, (R.sub.15).sub.r -phenyl, (R.sub.15).sub.r -naphthyl, or (R.sub.15).sub.r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and PA1 R.sub.15 is independently H, F, Cl, Br, I, NO.sub.2, N(R.sub.8).sub.2, N(R.sub.8)COR.sub.8, NR.sub.8 CON(R.sub.8).sub.2, OH, OCOR, ORE, CN, COOH, COOR.sub.8 an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons. PA1 X is --O--CO--, --NH--CO--, --CSNH, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --C.ident.--C, --CH.sub.2 --NH--, --COCH.sub.2 --, --NHCS--, --CH.sub.2 S--, --CH.sub.2 O--, --OCH.sub.2 --, --NHCH.sub.2 -- or --CR.sup.5.dbd.CR.sup.6 --; PA1 R.sup.m and R.sup.k are independently hydrogen, halogen, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkyloxy or nitro; PA1 n is zero or one; PA1 R.sup.4 is --(CH.sub.2).sub.t --Y; PA1 R.sup.1 is --CO.sub.2 Z, --C.sub.1-6 alkyl, CH.sub.2 OH, --CONHR.sup.y or CHO; PA1 R.sup.2 and R.sup.3 are independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.a and R.sup.b are independently hydrogen or C.sub.1-6 alkyl; but when n is one, R.sup.a and R.sup.b together can form a radical of the formula ##STR13## PA1 Y is phenyl or naphthyl and both radicals can be optionally substituted with one to three same or different C.sub.1-6 alkyl or halogen groups; PA1 Z is hydrogen or C.sub.1-6 alkyl; PA1 R.sup.5,R.sup.6 and R.sup.y are independently hydrogen or C.sub.1-6 alkyl; and PA1 t is zero to six. PA1 X is --O--CO--, --NH--CO--, --CSNH, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --C.ident.C--, --CH.sub.2 --NH--, --COCH.sub.2 --, --NHCS--, --CH.sub.2 S--, --CH.sub.2 O--, --OCH.sub.2 --, --NHCH.sub.2 -- or --CR.sup.5.dbd.CR.sup.6 --; PA1 R.sup.m and R.sup.k are independently hydrogen, halogen, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkyloxy or nitro; PA1 n is zero or one; PA1 A is --NH(CH.sub.2).sub.m --, --S--, --SO--, --SO.sub.2 --, --O--, --C.ident.C--, --CR.sup.8 R.sup.9, --CR.sup.8.dbd.CR.sup.9 --, phenyl, phenyl substituted by a C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, CO.sub.2 R.sup.8, --(CH.sub.2).sub.m OR.sup.8, --(CH.sub.2).sub.m NR.sup.9 R.sup.8, or --COR.sup.10 group, naphthyl, naphthyl substituted by a C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, CO.sub.2 R.sup.8, --(CH.sub.2).sub.m OR.sup.8, --(CH.sub.2).sub.m NR.sup.8 R.sup.9 or --COR.sup.10, or heteroaryl; PA1 Q is phenyl, naphthyl or heteroaryl, said phenyl, naphthyl or heteroaryl group being optionally substituted by one to three same or different C.sub.1-6 alkyl, C.sub.1-6 fluoroalkyl, C.sub.1-6 alkoxy, halogen, CO.sub.2 R.sub.11, --(CH.sub.2).sub.q OR.sup.11, --(CH.sub.2).sub.q NR.sup.11 R.sup.12, --NHCOR.sup.13 or --COR.sup.13 with the proviso that when A is --S--, --SO--, --SO.sub.2 -- or --O--, then Q is a phenyl, naphthyl or heteroaryl group substituted by one to three halogen, C.sub.1-6 fluoroalkyl, CO.sub.2 R.sup.11, --(CH.sub.2).sub.q OR.sup.11, --(CH.sub.2).sub.q NR.sup.11 R.sup.12, --NHCOR.sup.13 or --COR.sup.13 ; PA1 R.sup.5 and R.sup.6 are each independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.8 and R.sup.9 are each independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.10 and R.sup.13 are each independently hydrogen, C.sub.1-6 alkyl or C.sub.1-6 fluoroalkyl; PA1 R.sup.11 and R.sup.12 are each independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.a and R.sup.b are independently hydrogen or C.sub.1-6 alkyl; but when n is one, PA1 R.sup.a and R.sup.b together can form a radical of the formula ##STR15## PA1 Z is hydrogen, C.sub.1-6 alkyl, benzyl, p-methoxybenzyl, allyl or trimethylsilylethyl; PA1 m and q are independently 0 to 2; PA1 p is 0 or 1 with the proviso that when p is 0 then Q is phenyl, naphthyl or heteroaryl substituted by one to three --(CH.sub.2).sub.q OR.sup.11, --(CH.sub.2).sub.q NR.sup.11 R.sup.12, or --COR.sup.13 PA1 R.sup.2 and R.sup.3 are each independently hydrogen or C.sub.1-6 alkyl; PA1 R.sup.1 is --CO.sub.2 Z, C.sub.1-6 alkyl, --CH.sub.2 OH, --CONHR.sup.7 or CHO; PA1 R.sup.7 is hydrogen or C.sub.1-6 alkyl; PA1 provided that when X is --C.ident.C--, A is not --CR.sup.8.dbd.CR.sup.9 -- or --C.ident.C--.
These compounds are reported to have retinoid-like activity and to be useful for preventing and/or treating various skin disorders such as acne, psoriasis and damage from irradiation, for treatment of various tumors and non-malignant proliferative skin diseases and for treatment of rheumatic diseases such as rheumatoid arthritis.
The present inventors have discovered that certain compounds included within the scope of EP 661,259A1 and U.S. Pat. No. 5,618,839 are retinoid antagonists, i.e., they bind to all three RAR retinoic acid receptor subtypes (.alpha., .beta. and .gamma.) but do not activate at least two of the three subtypes when tested in a standard transactivation assay. These retinoid antagonist compounds have the general formula ##STR3##
or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof, in which
U.S. Pat. No. 5,534,261 discloses that retinoids, particularly all-trans retinoic acid, can be used to minimize or prevent adhesion formation following surgery. There is no illustration or suggestion, however, that a retinoid antagonist compound would have this same utility.
Published patent application WO 97/09297 discloses retinoid antagonist compounds of the general formula ##STR5##
wherein X is S, O or NR.sup.1 where R.sup.1 is H or alkyl of 1-6 carbons, or X is [C(R.sub.1).sub.2 ].sub.n where R.sub.1 is independently H or alkyl of 1 to 6 carbons, and n is 0, 1 or 2;
--N.dbd.N--, PA2 --N.dbd.CR.sub.1 --, PA2 --CR.sub.1.dbd.N, PA2 --(CR.sub.1.dbd.CR.sub.1).sub.n' where n' is 0 or an integer of 1-5, PA2 --CO--NR.sub.1 --, PA2 --CS--NR.sub.1 --, PA2 --NR.sub.1 --CO, PA2 --NR.sub.1 --CS, PA2 --COO--, PA2 --OCO--, PA2 --CSO--, or PA2 --OCS--; PA2 --N(O).dbd.N--, PA2 --N.dbd.N(O)--, PA2 --N.dbd.CR.sub.1 --, PA2 --CR.sub.1.dbd.N, PA2 --(CR.sub.1.dbd.CR.sub.1).sub.n' -- where n' is an integer having the value 0-5, PA2 --CO--NR.sub.1 --. PA2 --CS--NR.sub.1 --. PA2 --NR.sub.1 --CO, PA2 --NR.sub.1 --CS--, PA2 --COO--, PA2 --OCO--, PA2 --CSO--, PA2 --OCS--, PA2 --CO--CR.sub.1.dbd.CR.sub.1 --; PA2 --N(O).dbd.N--, PA2 --N.dbd.N(O)--, PA2 --N.dbd.CR.sub.1 --, PA2 --CR.sub.1.dbd.N, PA2 --(CR.sub.1.dbd.CR.sub.1).sub.n' -- where n' is an integer having the value 0-5, PA2 --CO--NR.sub.1 --. PA2 --CS--NR.sub.1 --. PA2 --NR.sub.1 --CO, PA2 --NR.sub.1 --CS--, PA2 --COO--, PA2 --CSO--, PA2 --OCS--, PA2 --CO--CR.sub.1.dbd.CR.sub.1 --;
Also disclosed in this publication as retinoid antagonist compounds are compounds of the general formula ##STR6##
wherein X is S, O or NR.sup.1 where R.sup.1 is H or alkyl of 1-6 carbons, or
The above-mentioned retinoid antagonist compounds are said to be useful for preventing certain undesired side effects of retinoids which are administered for the treatment or prevention of certain diseases or conditions. They are also said to be useful in the treatment of acute or chronic toxicity resulting from overdose or poisoning by retinoid drugs or Vitamin A.
The present inventors have surprisingly found that retinoid antagonist compounds, particularly the retinoid antagonists disclosed above which are generically taught in EP 661,259 A1 and in U.S. Pat. No. 5,618,839, have utility in preventing or minimizing post-surgical adhesion formation and, in fact, are significantly more active for this use than the retinoid agonists described in U.S. Pat. No. 5,534,261.
In another aspect, the present inventors have prepared a novel series of substituted (5,6)-dihydronaphthalenyl compounds which also are potent retinoid antagonists. These new compounds display the utilities of the retinoid antagonist compounds described in U.S. Pat. No. 5,618,839 and EP 661,259 A1, and also possess the ability to prevent or minimize post-surgical adhesion formation. This new series of retinoid antagonists is generically defined by the formula ##STR7##
or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof, in which
provided that when X is --C.ident.C--, A is not --CR.sup.8.dbd.CR.sup.9 -- or --C.ident.C--.
The novel compounds of formula II are distinguished from those in WO 97/09297 by the presence of the linking group "A" between the core skeleton and the terminal aryl or heteroaryl substituent.
U.S. Pat. No. 5,648,514 discloses retinoids of the formula ##STR9##
wherein
The novel compounds of formula II are distinguished from those in U.S. Pat. No. 5,648,514 by the nature of the linking group "X" which is not C.ident.C linked to the central benzene ring when A is --CR.sup.8.dbd.CR.sup.9 -- or --C.ident.C--.
Published patent application WO 97/48672 discloses retinoids of the formula ##STR10##
wherein X.sub.1 is [C(R.sup.1).sub.2 ].sub.n where R.sub.1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 to 2;
wherein X.sub.1 is [C(R.sub.1).sub.2 ].sub.n where R.sub.1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
The novel compounds of formula II may be distinguished from those in WO 97/48672, formula 5, by the nature of the linking group "A" versus "X.sub.2 ". The formula II compounds may be distinguished from those in WO 97/48672, formula 6, by the inclusion of the linking group "A" between the core skeleton and the terminal aryl or heteroaryl substituent.